Clinicopathologic characterization of enfortumab vedotin-associated cutaneous toxicity in patients with urothelial carcinoma

Abstract

To the Editor: Enfortumab vedotin (EV), an antibody-drug conjugate the United States Food and Drug Administration approved in December 2019 for third-line treatment of locally advanced or metastatic urothelial cancer, is composed of an anti–nectin-4 antibody linked to the microtubule inhibitor monomethyl auristatin E. Nectin-4 is expressed in several epithelial malignancies as well as in normal skin and adnexal structures.1Rosenberg J. Sridhar S.S. Zhang J. et al.EV-101: a phase I study of single-agent enfortumab vedotin in patients with nectin-4-positive solid tumors, including metastatic urothelial carcinoma.J Clin Oncol. 2020; 38: 1041-1049Crossref PubMed Scopus (78) Google Scholar Approximately 45% of patients in EV phase I clinical trials experienced rash as an adverse event,1Rosenberg J. Sridhar S.S. Zhang J. et al.EV-101: a phase I study of single-agent enfortumab vedotin in patients with nectin-4-positive solid tumors, including metastatic urothelial carcinoma.J Clin Oncol. 2020; 38: 1041-1049Crossref PubMed Scopus (78) Google Scholar but only a few case reports describe variable clinicopathologic presentations.2Wu S. Adamson A.S. Cutaneous toxicity associated with enfortumab vedotin treatment of metastatic urothelial carcinoma.Dermatol Online J. 2019; 25 (13030/qt4j44w7w6)Crossref Google Scholar, 3Keerty D. Graham L. Haynes E. Hembree T.N. Flexural exanthema from enfortumab vedotin.Cureus. 2020; 12: e8102PubMed Google Scholar, 4Sasaki R. Fujimura T. Lyu C. Aiba S. Severe eczematoid and lichenoid eruption with full-thickness epidermal necrosis developing from metastatic urothelial cancer treated with enfortumab vedotin.J Dermatol. 2020; 47: 1436-1438Crossref PubMed Scopus (9) Google Scholar We therefore sought to further characterize the distinctive clinical and histopathologic features of EV-associated cutaneous toxicity. After Institutional Review Board approval, we retrospectively identified 8 patients referred to our supportive dermato-oncology clinic who received EV from 2017 to 2020. All patients were treated for metastatic urothelial carcinoma, and 7 received prior or concurrent anti-programmed death-1 therapy. Complete demographics and clinicopathologic features are detailed in Supplemental Table I (available via Mendeley at https://data.mendeley.com/datasets/8wx2hd5twc/3). Median time of rash onset was 12 days (range, 4 days-2 months). Dermatitis was characterized by smooth and scaly erythematous papules and thin plaques predominantly in flexural and acral areas (Fig 1; Supplemental Figs 1 and 2), with occasional vesicles/bullae (n = 4 of 8). Prominent hyperpigmentation and superficial desquamation were noted in Fitzpatrick skin types II to V (n = 3 of 8). All patients reported significant pruritus, 7 had epiphora or dry eyes, and 4 had scalp alopecia. Histopathology, where available (n = 4 of 8), demonstrated vacuolar interface dermatitis or epidermal spongiosis, vesiculation, and necrosis. Biopsy specimens from 3 patients showed prominent ring and starburst mitoses and dyskeratosis within the epidermis, eccrine ducts, and follicular epithelium (Fig 2, Supplemental Fig 3). Results of direct immunofluorescence studies, performed for vesiculobullous lesions in 2 patients, were negative. Five patients interrupted treatment and/or stopped EV for reasons that included skin toxicity, 3 patients responded to topical steroids with a full Common Terminology Criteria for Adverse Events grade reduction in rash and pruritus,2Wu S. Adamson A.S. Cutaneous toxicity associated with enfortumab vedotin treatment of metastatic urothelial carcinoma.Dermatol Online J. 2019; 25 (13030/qt4j44w7w6)Crossref Google Scholar,3Keerty D. Graham L. Haynes E. Hembree T.N. Flexural exanthema from enfortumab vedotin.Cureus. 2020; 12: e8102PubMed Google Scholar and 4 patients required a short course of systemic corticosteroids (oral prednisone 0.5-1 mg/kg daily) (Supplemental Table I). No severe cutaneous adverse reactions were observed. In this series of 8 patients with urothelial carcinoma with EV-associated cutaneous toxicity, the clinical eruption resembled nonallergic toxic erythema of chemotherapy, occurring within days of drug exposure and predominantly affecting flexural and acral sites. Some patients demonstrated prominent hyperpigmentation, reflecting the interface dermatitis seen histopathologically.2Wu S. Adamson A.S. Cutaneous toxicity associated with enfortumab vedotin treatment of metastatic urothelial carcinoma.Dermatol Online J. 2019; 25 (13030/qt4j44w7w6)Crossref Google Scholar,4Sasaki R. Fujimura T. Lyu C. Aiba S. Severe eczematoid and lichenoid eruption with full-thickness epidermal necrosis developing from metastatic urothelial cancer treated with enfortumab vedotin.J Dermatol. 2020; 47: 1436-1438Crossref PubMed Scopus (9) Google Scholar In our series, intraepithelial ring mitoses were a common histopathologic feature that has not been previously reported, to our knowledge, in EV-associated cutaneous toxicity. Binding of EV to cutaneous nectin-4 may result in keratinocyte microtubule disruption by microtubule inhibitor monomethyl auristatin E, mimicking the mechanism of action of taxane chemotherapies. Consequently, our patients demonstrated several histopathologic similarities to taxane-induced toxic erythema of chemotherapy, including the characteristic ring or starburst mitotic figures, interface dermatitis, and epidermal dysmaturation.5Prieto-Torres L. Llamas-Velasco M. Machan S. et al.Taxanes-induced cutaneous eruption: another histopathologic mimicker of malignancy.J Eur Acad Dermatol Venereol. 2016; 30: 638-644Crossref PubMed Scopus (10) Google Scholar Ring mitoses in eccrine ducts and hair follicles are suggestive of nectin-4 expression and EV activity in these structures, potentially explaining the toxic erythema of chemotherapy-like distribution in eccrine gland-enriched areas. In summary, EV-associated cutaneous toxicity may present as a predominantly flexural and acral eruption characterized by interface dermatitis and intraepithelial ring mitoses. Prompt recognition and management with topical and/or systemic corticosteroids may allow continued EV treatment, which is often used as a last-line oncologic therapy. Dr Kwong is a consultant for Genentech, Oncoderm, Happy 2nd Birthday, and is on the advisory board of Kyowa Kirin. Drs Hirotsu, Rana, Wang, Raghavan, Rieger, Srinivas, Fan, Novoa, and Zaba have no conflicts of interest to disclose.